Glucose-6-phosphate dehydrogenase deficiency in the Han Chinese population: molecular characterization and genotype–phenotype association throughout an activity distribution

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common hereditary disorder in China. The existing prevalence and molecular epidemiology of G6PD deficiency in China were geographically limited. In this study, the spectrum of G6PD gene mutations was well characterized in a large and diverse population all over the country; and the correlation of genotype and enzyme activity phenotype was explored for the first time. The results showed that the overall prevalence of G6PD deficiency in China was 2.10% at the national level. The top six common mutations were c.1388 G>A, c.1376 G>T, c.95 A>G, c.392 G>T, c.871 G>A and c.1024 C>T, accounting for more than 90% of G6PD deficient alleles. Compound mutation patterns were frequently observed in females with severe deficiency. The distribution of G6PD activities depended on the type of mutation patterns and genders. Hemizygote, homozygote, and compound heterozygote were predominantly associated with severe G6PD deficiency, whereas heterozygotes with single mutation mainly presented moderate enzyme deficiency. A significant gap between G6PD activities in hemizygous and normal males was observed, and yet, the overall distribution of that in females carrying missense mutations was a continuum from G6PD severely deficient to normal. This is the first report of discussing the association between G6PD genetic variants in the Chinese and enzyme activity phenotypes.

Glucose-6-phosphate dehydrogenase mutations in malaria endemic area of Thailand by multiplexed high‐resolution melting curve analysis

“…Additionally, 5 males and 58 females carrying G6PD Mahidol and 3 females carrying G6PD Canton showed G6PD activity even greater than the 70 % activity cut-off (7 U/gHb). Similar findings were previously described in genotype–phenotype association studies [ 31 , 32 ]. This is mainly attributable to the fact that the degree of deficiency and vulnerability to haemolysis vary substantially among the different genotypes.…”

“…Although other multiplex systems for genetic analysis are currently available, they might be unsuitable for large population screening. The G6PD gene chip kit can detect 13–14 mutations common in Chinese populations, but must be combined with a hybridization kit, which is time-consuming [ 32 , 65 ]. The DiaPlexC™ (Asian type) can simultaneously detect eight mutations, but requires an additional gel electrophoresis step to check the amplified products [ 42 ].…”

“…To date, over 200 G6PD variants have been identified, which form genotypes associated with differences in the degree of deficiency and vulnerability to haemolysis [ 30 ]. Moreover, G6PD activities vary among G6PD-deficient individuals carrying the same genotype [ 31 , 32 ].…”

Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

“…However, based on the same principle, 71.8% cases with c.1388G>A and 65.7% cases with c.871G>A in our study displayed residual enzymatic activities associated with class III variants (Figure 5). Whereas, in a study conducted in Shenzhen city, a city in South China that is just 600 km from Xiamen, more than 95% of cases with these two variants displayed residual enzymatic activities associated with class II variants (He et al, 2020). Many factors could be contributive to the highly heterogeneous phenotypes among individuals with the same genotype; however, the exact mechanism remains to be elucidated.…”

“…To date, more than 200 pathogenic G6PD variants have been identified, most of which are single nucleotide substitutions. The variant spectrum differs among regions and populations (Minucci et al, 2012;Peng et al, 2015;Gómez-Manzo et al, 2016a;Chen et al, 2018;He et al, 2020). Pathogenic G6PD variants disrupt enzyme synthesis, stability, or function, resulting in an enzyme deficiency in the red blood cells and the related clinical presentations (Gómez-Manzo et al, 2014;Gómez-Manzo et al, 2016b;Ramírez-Nava and Ortega-Cuellar, 2017;Hwang and Mruk 2018;Bahr et al, 2020).…”